Minimally Invasive Colorectal Resection Is Associated with Decreased Levels of the Tumor Growth Inhibitor Plasma Angiopoietin-Like Protein 4 (angptl4) During the First Month After Surgery Which May Promote Angiogenesis and Tumor Growth

Introduction: Angiopoietin-like protein 4 (ANGPTL4) is a secreted protein of the angiopoietin-like family. ANGLPT4 mRNA is frequently found in and near the necrotic areas of tumors and is upregulated in both epithelial tumors and in the endothelial cells (EC’s) of tumor vessels. Expression is regulated by hypoxia in both EC’s and tumor cells; ANGLPT4 accumulates in the extracellular matrix (ECM) of hypoxic EC’s. ECM-bound ANGPTL4 reduces EC adhesion, and decreases EC migration and sprouting. ANGPTL4 also inhibits VEGF-induced vascular permeability and angiogenesis, possibly preventing metastasis by inhibiting tumor cell motility and invasiveness. Perioperative plasma ANGPTL4 levels in cancer patients have not been studied. Our aim was to assess plasma levels during the first month after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC).Methods: Plasma for this study was obtained from an IRB-approved perioperative plasma and data bank; only cancer patients who underwent elective minimally invasive colorectal resection (MICR) were eligible. Blood samples had been obtained preop and at varying postop time points and were stored at -800C. Only patients for whom preop, POD 3, and at least 1 late postop plasma sample (POD7-67) were available were included in this study. The late samples were bundled into 4 time periods (POD7-13, POD14-20, POD21-27, and POD 28-67) and considered as single time points. ANGPT4 levels were determined in duplicate via ELISA and the results are reported as mean ±SD after logarithmic transformation of the data to a normal distribution. The paired t-test was used for statistical analysis with significance set at p<0.01 (after Bonferoni correction).Results: 80 MICR patients met the inclusion criteria (43 males/37 female, mean age 66.8 ±13.2 years). Twenty nine percent of patients had rectal tumors and 71% colonic lesions. Mean incision length was 7.1±3.2cm, mean operative time was 241.2±95.0 min., and mean length of stay was 5.9±2.3 days. Final cancer stage breakdown was: stage I, n=24; stage II, n=27; stage III, n=27; and stage IV, n=2. Regarding ANGPTL4 levels, the “n” for each comparison varies widely based on postop plasma availability. The mean PreOp ANGPTL4 level was 247.2 ±230.7 ng/ml for the entire group. Significantly lower mean plasma levels (p<0.001) were noted on POD 3 (161.4±140.4ng/ml, n=80), POD7-13 (144.6±134.5 ng/ml, n=46), POD14-20 (139.0±117.8 ng/ml,n=27), POD21-27 (138.9±202.4,n=20), and for the POD 28-67 (160.1±179.0,n=42) time points when compared to the mean preop results. Conclusion: Plasma ANGPTL4 levels remain significantly lower than baseline for over a month after MICR. The cause(s) for this notable persistent decrease is unclear. Possible reasons are: 1) removal of the cancer, 2) systemic alterations related to wound healing following surgical trauma. Since ANGPTL4 has many angiogenesis inhibiting effects, this persistent decline after MICR likely promotes wound angiogenesis and may encourage neovascularization in residual micrometastases that remain in some patients after removal of the primary tumor. Further studies are warranted.